Abstract
Cytomegalovirus (CMV) is a β-herpesvirus that establishes a lifelong latent or persistent infection. A hallmark of chronic CMV infection is the lifelong persistence of large numbers of virus-specific CD8+ effector/effector memory T cells, a phenomenon called “memory inflation”. How the virus continuously stimulates these T cells without being eradicated remains an enigma. The prevailing view is that CMV establishes a low grade “smoldering” infection characterized by tiny bursts of productive infection which are rapidly extinguished, leaving no detectable virus but replenishing the latent pool and leaving the immune system in a highly charged state. However, since abortive reactivation with limited viral gene expression is known to occur commonly, we investigated the necessity for virus reproduction in maintaining the inflationary T cell pool. We inhibited viral replication or spread in vivo using two different mutants of murine CMV (MCMV). First, famcyclovir blocked the replication of MCMV encoding the HSV Thymidine Kinase gene, but had no impact on the CD8+ T cell memory inflation once the infection was established. Second, MCMV that lacks the essential glycoprotein L, and thus is completely unable to spread from cell to cell, also drove memory inflation if the virus was administered systemically. Our data suggest that CMV which cannot spread from the cells it initially infects can repeatedly generate viral antigens to drive memory inflation without suffering eradication of the latent genome pool.
Highlights
Cytomegalovirus is a b-herpesvirus that establishes life-long, persistent infections in healthy people, and is associated with significant morbidity in immunosuppressed individuals
We have tested this model by blocking the replication or spread of murine cytomegalovirus (MCMV) and found, surprisingly, that accumulation of virus-specific T cells occurs independently of viral replication
Acyclovir is a guanosine analogue that acts as a DNA chain terminator when it is phosphorylated by herpes simplex virus thymidine kinase (TK) [26]
Summary
Cytomegalovirus is a b-herpesvirus that establishes life-long, persistent infections in healthy people, and is associated with significant morbidity in immunosuppressed individuals. Long-term CMV carriage is characterized by viral latency in many organs, but the variety of cells that can harbor latent virus is unclear. Hematopoietic progenitor cells in humans [1] and liver sinusoidal endothelial cells in the mouse [2] have been shown to harbor latent virus, but in both species it is likely that other cellular sites exist, and their relative importance is unknown (reviewed in [3,4]). Abortive reactivation (viral gene expression that does not result in virion production) is common, at least in the mouse model and CD8+ T cells have been shown to contribute by preventing the cascade of lytic cycle gene expression from progressing past the immediate early (IE) or early (E) gene stages [5,6]. How the latent pool of virus is maintained through this process of reactivation and immune recognition remains unclear
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